Soticlestat Shows Mixed Results in Phase 3 Studies of Dravet and Lennox-Gastaut Syndrome

Topline data from Takeda’s SKYLINE (NCT04940624) and SKYWAY (NCT05163314) phase 3 studies assessing soticlestat, also known as TAK-935, in patients with refractory Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) showed mixed findings on the primary end point of convulsive seizure reduction. The company noted that it will engage with regulatory authorities to discuss the totality of the current data to determine next steps for TAK-935.¹

In SKYLINE (n = 144), which featured patients with refractory DS, soticlestat almost missed the primary end point of reduction from baseline in convulsive seizure frequency as compared with placebo (P = 0.06). For SKYWAY (n = 270), soticlestat missed its primary end point of reduction in Major Motor Drop (MMD) seizure frequency as compared with placebo in patients with refractory LGS. As for secondary end points in SKYLINE, soticlestat displayed clinically meaningful and nominally significant results in responder rate, measures of caregiver and clinician global impression of improvement, and seizure intensity and duration scales over 16 weeks (all, P ≤ .008).

“We are grateful to all the participants and their families, as well as investigators and clinical staff for their participation in these important studies,” Sarah Sheikh, MSc, BM, BCh, MRCP, head of the Neuroscience Therapeutic Area Unit and head of global development at Takeda, said in a statement.¹ “Even with currently available therapies, we know that many patients with developmental encephalopathies like DS and LGS still experience persistent unmet need across multiple dimensions, such as seizure burden and treatment tolerability. While we would have wished for more declarative results on the primary end points, we are encouraged by positive outcomes seen in the totality of the data and are looking forward to engaging health authorities to determine the best path forward.”

Top Clinical Takeaways

Soticlestat nearly met the primary end point in the SKYLINE study for reducing convulsive seizure frequency in DS patients, but missed the primary end point in the SKYWAY study.
Secondary end points in the SKYLINE study showed clinically meaningful improvements, including seizure intensity, duration, and caregiver and clinician global impressions of improvement.
Despite mixed primary results, the overall positive data from the studies will lead Takeda to engage with regulatory authorities to discuss the future of soticlestat.

SKYLINE is a global, multicenter, randomized, double-blind, placebo-controlled, parallel group study aimed to assess the efficacy, safety, and tolerability of soticlestat as adjunctive therapy in pediatric and young adult patients with DS. The primary end point was the percentage change from baseline in convulsive seizure frequency per 28 days in participants who received soticlestat as compared with placebo in the full treatment period. The key secondary end points included assessment of effects on treatment response, Caregiver Global Impression of Improvement (Care GI-I), CGI-I, CGI-I Non-Seizure Symptoms, QI-Disability, CGI-I seizure intensity and duration.

SKYWAY global study designed to investigate the efficacy, safety, and tolerability of soticlestat as adjunctive therapy in pediatric and adult patients with LGS, is built exactly the same as SKYLINE, just with a different patient population. The primary end point was percent change from baseline in MMD seizure frequency per 28 days while the key secondary end points included evaluation of effects on treatment response, Care GI-I, CGI-I, CGI-I Non-Seizure Symptoms, QI-Disability, CGI-I seizure intensity and duration.

In SKYLINE and SKYWAY, the study treatment period lasted 16 weeks including a 4-week titration period and 12-week maintenance period. The patients in these trials were randomized 1:1 to receive either soticlestat or matching placebo twice daily (BID) added to current antiseizure therapy administered orally or via enteral tube feeding. Investigators had patients start soticlestat at 100 mg BID or weight equivalent dose for 7 days and had treatment titrated up weekly, based on tolerability, up to 300 mg BID or weight equivalent dose. Upon study completion, participants had the option to voluntarily enroll in an open-label extension study (ENDYMION; NCT03635073).

In both studies, over the 16-week period, some of the prespecified subgroups of patients demonstrated nominally significant treatment effects on the primary and secondary efficacy end points of caregiver and clinician global impression of improvement, and seizure intensity and duration scales. Overall, soticlestat was generally well tolerated in these studies and had a safety profile consistent with the results from previous studies. In its release, the company noted that further analyses are being conducted with the candidate drug.

In the phase 2 ELEKTRA (NCT03650452) study, soticlestat showed a statistically significant reduction of seizures from baseline compared with placebo (P = .002) in the combined DS and LGS study population during the full treatment period.² In the DS cohort, a statistically significant reduction in convulsive seizure frequency from baseline compared with placebo (P = .0007) was achieved. In a pooled analysis of SKYLINE and the DS cohort from ELEKTRA, soticlestat also revealed a reduction from baseline in convulsive seizure frequency compared with placebo (P = 0.001).